Natural Killer (NK) cells are primary effector cells of the innate immune response and play a critical role in the control of viral replication in several disease models. Depletions or deficiencies of NK cells lead to significantly more severe viral disease and death in both mice and humans. Killer immunoglobulin-like receptors (KIRs) interact with HLA class I ligands and play a central role in the regulation and activation of naturl killer (NK) cells. The interaction between KIRs and their HLA class I ligands can thus have a profound impact on the efficacy of NK cell-mediated control of viral pathogenesis and has been demonstrated for a number of chronic viral infections. Very little is known about the involvement of NK cells in regulating dengue virus infections. We have found that a CD8 T cell epitope on the non-structural protein 1 (NS1) of dengue interacts with a well characterized inhibitory receptor KIR3DL1 on NK cells. In this application, we will use the antigen-specific tetramers and peptides to dissect the interaction with KIR3DL1 and determine how dengue virus modulates the function of this important subset of NK cells. The studies outlined in this application will provide a better understanding of the importance of KIR-MHC class I interactions on NK cells and provide the rationale to target this innate arm of the immune response to control dengue virus replication.